Astroglia Pathobiology in the Neurodegenerative Sequelae of Repetitive Mild Traumatic Brain Injury
Abstract
For many years TBI has been known to be a risk factor for later life neurodegenerative diseases, such as Alzheimer's Disease Related Dementias (ADRD), but the precise nature of how TBI leads to or precipitates these conditions (or different pathological substrates) is not understood. We have spent years developing and characterizing mouse models of r-mTBI that demonstrate lifelong behavioral and neuropathological features of human TBI and are thus relevant models in which to generate data that will translate to human patients. In our mouse model, we observe dramatic increases in reactive astrocyte cells, and these increases last for life. We thus hypothesized that repetitive mTBI induces significant and persistent changes to reactive astrocyte populations after injury and that these reactive astroglial responses are critical to TBI neurodegeneration and, in the context of other potentially pathogenic proteins such as tau, distinct ADRD proteinopathies can be triggered. Here we propose neuropathological analyses of human autopsy cases of TBI, ADRD, and from the brains of normal mice and mice producing potentially pathological tau proteins (in neurons vs astrocytes), at a range of timepoints following repetitive mild TBI. We have analyzed astrocyte lesions in tissue from our mouse models and observe qualitative and quantitative changes to astrocyte morphologies following injury. We explored the role of astrocytes in inducing and driving pathogenesis by utilizing novel mechanistic approaches in our mouse models, involving intracerebral injections of TBI/sham astroglial secretome into nave mice, and utilizing ex vivo functional assays to closely study whether reactive astrocytes in the injured brain can activate ex vivo microglial inflammatory response(s).
Document Details
- Document Type
- Technical Report
- Publication Date
- Nov 01, 2023
- Accession Number
- AD1226559
Entities
People
- Fiona Crawford
- Joseph Ojo
- Lauren Horne